Summary/Abstract Human subjects consuming a grape based polyphenol-rich botanical mixture demonstrate significant differences in the presence and abundance of bioactive phenolic acids with known anti-inflammatory health benefits. We hypothesize that interpersonal differences in subsets of the gut microbiota critical for processing and bioavailability of dietary polyphenols affect bioavailability of bioactive phenolic metabolites, particular phenolic acids, to peripheral and brain tissues, and therefore, impact the potential health benefits of polyphenol-rich botanical supplements, including the preservation of psychological and cognitive resilience under stress conditions, which is the focus of our Botanical Dietary Supplement Research Center application. Each individual harbors a unique set of roughly 100 different bacterial species in their gut microbiota some of which increase the bioavailability and diversity of bioactive phenolic metabolites in the periphery and in the brain in the context of humans or animal models consuming a polyphenol-rich diet. To identify the human gut microbes that modulate phenolic acid bioavailability, we will use combinatorial gnotobiotics and statistical modeling to dissect the interrelationship between a polyphenol-rich botanical supplement, gut microbiota, and phenolic acid bioavailability. We will transplant the microbiota of different human donors into gnotobiotic mice given the botanical supplements to quantify the role of interindividual variation in microbiota composition on the bioavailability of phenolic metabolites, with an emphasis on those verified to modulate psychological and/or cognitive resilience. We will then target specific human donor microbiotas for high-throughput robotic isolation of individual bacterial strains using methods we developed for isolating, archiving, and retrieving large numbers of gut microbes. We will use a combinatorial gnotobiotic screening method to colonize individual gnotobiotic mice with combinations of strains isolated from the human donors of interest and apply statistical modeling and feature selection algorithms to identify microbial strains that modulate bioactive phenolic acids of interest in the serum and the brain. These studies will identify individual strains or subsets of the microbiota critical for generation of phenolic acids that play key roles in modulating the efficacy of the botanicals in preserving psychological and/or cognitive resilience under challenges by stress conditions. From these results, we will generate a human-derived probiotic cocktail validated to modulate biologically available, bioactive phenolic metabolites established to have important biological functions.